Method for the production of optically active 2-amino 2-chloro, 2 hydroxy or 2-alkoxy-1-alcohols

ABSTRACT

The invention relates to a process for preparing optically active 2-amino-, 2-chloro-, 2-hydroxy- or 2-alkoxy-1-alcohols by catalytically hydrogenating appropriate optically active 2-amino-, 2-chloro-, 2-hydroxy- and 2-alkoxycarboxylic acids or their acid derivatives in the presence of catalysts comprising palladium and rhenium or platinum and rhenium.

CROSS REFERENCE TO RELATED APPLICATION

The present application is a National Stage application ofPCT/EP2003/009513, filed Aug. 28, 2003, which claims priority fromGerman Patent Application No. DE 102 41 292.8, filed Sep. 4, 2002.

The present invention relates to an improved process for preparingoptically active 2-amino-, 2-chloro-, 2-hydroxy- or 2-alkoxy-1-alcoholsby catalytically hydrogenating optically active 2-amino-, 2-chloro-,2-hydroxy- or 2-alkoxycarboxylic acids or their acid derivatives.

As disclosed by EP-A-696 575 and EP-A-717 023, optically active2-aminocarboxylic acids and 2-hydroxycarboxylic acids can behydrogenated to optically active 2-amino-1-alkanols and 1,2-alkanediolsin the presence of ruthenium catalysts such as elemental ruthenium,ruthenium oxides and hydroxides or ruthenium on supports. In a reactionbetween 80 and 100° C., an enantiomeric excess of up to 98.5% e.e. ismaintained.

According to WO 99/38838, the yields and enantiomeric excesses of2-amino-1-alkanols can also be increased by hydrogenating thecorresponding 2-aminocarboxylic acids in the presence of mineral acidsand ruthenium catalysts which comprise from one to two further elementsof atomic number from 23 to 82. Particular preference is given toruthenium/rhenium catalysts whose use leads to the retention ofenantiomeric excesses of up to 99.9% e.e.

According to WO 99/38824, it is also possible to increase the yields andenantiomeric excesses of 1,2-alkanediols by using ruthenium catalystswhich comprise one or two further elements of atomic numbers from 23 to82. Particular preference is given to the addition of rhenium.

WO 99/38613 describes a process for preparing particularly advantageouscatalysts which comprise ruthenium and at least one other element ofatomic number from 23 to 82 and their use for hydrogenations. Theprocess comprises combining a slurry of a ruthenium compound which has aspecific surface area of from 50 to 300 m²/g with a solution of at leastone metal compound. Particular preference is given to unsupportedruthenium/rhenium catalysts which are used for the preparation ofoptically active 2-aminoalcohols or 1,2-diols.

It is also known that optically active 2-amino- and 2-hydroxycarboxylicesters can be hydrogenated at 25° C. and 100 bar of hydrogen pressure inthe presence of catalysts consisting of rhodium and platinum and asolvent to corresponding optically active 2-aminoalcohols or 1,2-diolswith enantiomeric excesses of over 99.9% e.e. (M. Studer et al., Adv.Synth. Catal. 2001, 343, pages 802–808).

WO 98/52891 discloses the hydrogenation of aliphatic carboxylic acids,anhydrides, esters or lactones in the presence of platinum/rheniumcatalysts which comprise a further element such as molybdenum, silver orpalladium to the corresponding alcohols. This allows corrosion problemsto be avoided.

It is an object of the present invention to provide an improved processfor hydrogenating optically active 2-amino-, 2-chloro-, 2-hydroxy- and2-alkoxycarboxylic acids and their acid derivatives to the correspondingoptically active alcohols. The catalysts to be used for thehydrogenation should be easy to prepare, have a high activity and leadto high yields of productive value and enantiomeric excesses.

We have found that this object is achieved by a process for preparingoptically active 2-amino-, 2-chloro-, 2-hydroxy- or 2-alkoxy-1-alkanolsby catalytically hydrogenating appropriate optically active 2-amino-,2-chloro-, 2-hydroxy- and 2-alkoxycarboxylic acids or their acidderivatives, which comprises carrying out the hydrogenation in thepresence of catalysts comprising palladium and rhenium or platinum andrhenium.

In the process according to the invention, it is possible to use, forexample, optically active carboxylic acids or their derivatives of theformula I

-   -   where the radicals are defined as follows:

-   R¹: straight-chain or branched C₁–C₁₂-alkyl, C₇–C₁₂-aralkyl or    C₆–C₁₀-aryl, each of which may be substituted by NR³R⁴, OH, COOH    and/or further groups stable under the reaction conditions,

-   R²: hydrogen, straight-chain or branched C₁–C₁₂-alkyl or    C₃–C₈-cycloalkyl,

-   X: chlorine, NR⁵R⁶ or OR⁷,

-   R³, R⁴, R⁵ and R⁶:    -   each independently hydrogen, straight-chain or branched        C₁–C₁₂-alkyl, C₇–C₁₂-aralkyl, C₆–C₁₀-aryl, C₃–C₈-cycloalkyl or        C₃–C₈-cycloalkyl in which one CH₂ group is replaced by O or NR⁸,

-   R³ and R⁴ and also R⁵ and R⁶:    -   also each independently together —(CH₂)_(m)—, where m is an        integer from 4 to 7,

-   R¹ and R⁵:    -   also together —(CH₂)_(n)— where n is an integer from 2 to 6,

-   R⁷: hydrogen, straight-chain or branched C₁–C₁₂-alkyl or    C₃–C₈-cycloalkyl,

-   R¹ and R⁷:    -   also together —(CH₂)_(n)—, where n is an integer from 2 to 6 and

-   R⁸: hydrogen, straight-chain or branched C₁–C₁₂-alkyl,    C₇–C₁₂-aralkyl or C₆–C₁₀-aryl,    -   or their acid anhydrides and hydrogenate them to the        corresponding optically active alcohols.

The R¹ radicals may be widely varied and also bear, for example, from 1to 3 substituents stable under the reaction conditions, such as NR³R⁴,OH and/or COOH.

Examples of R¹ radicals include:

-   C₁–C₆-alkyls such as methyl, ethyl, propyl, 1-methylethyl, butyl,    1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl,    1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl,    1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,    1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,    1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,    2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl,    1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl,    1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl or    1-ethyl-2-methylpropyl,-   C₁–C₁₂-alkyl such as C₁–C₆-alkyl (mentioned above) or unbranched or    branched heptyl, octyl, nonyl, decyl, undecyl or dodecyl,-   C₇–C₁₂-aralkyls such as phenylmethyl, 1-phenylethyl 2-phenylethyl,    1-phenylpropyl, 2-phenylpropyl or 3-phenylpropyl,-   C₆–C₁₀-aryls such as phenyl, naphthyl or anthracenyl, each of which    may bear a substituent such as NR⁹R¹⁰, OH and/or COOH.

Examples of definitions of R² include the following:

-   hydrogen, straight-chain or branched C₁–C₁₂-alkyl (as specified    above) or C₃–C₈-cycloalkyl, e.g. cyclopropyl, cyclobutyl,    cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Instead of the carboxylic ester, it is also possible to use acidanhydrides as carboxylic acid derivatives.

The X radical is chlorine, NR⁵R⁶ or OR⁷ where R⁵ and R⁶, exactly like R³and R⁴, or R⁹ and R¹⁰, are each independently hydrogen, straight-chainor branched C₁–C₁₂-alkyl, especially C₁–C₆-alkyl, C₇–C₁₂-aralkyl orC₆–C₁₀-aryl, especially phenyl, or C₃–C₈-cycloalkyl (each as specifiedabove for the R¹ and R² radicals).

The R³ and R⁴, R⁵ and R⁶, and also R⁹ and R¹⁰ pairs may each beindependently combined to form —(CH₂)_(m) where m is an integer from 4to 7, in particular 4 or 5. A CH₂ group may be replaced by O or NR⁸.

The R¹ and R⁵ radicals may also together be —(CH₂)_(n)— where n is aninteger from 2 to 6.

The R⁷ radical is preferably hydrogen or straight-chain or branchedC₁–C₁₂-alkyl or C₃–C₈-cycloalkyl, more preferably methyl, ethyl,1-methylethyl, 1,1-dimethylethyl, hexyl, cyclohexyl or dodecyl. It mayalso be —(CH₂)_(n)— together with R¹ where n is an integer from 2 to 6.

The hydrogenation according to the invention provides the correspondingoptically active alcohols of the formula II

where R¹ and X are each as defined above.

Examples of useful starting materials include 2-amino-, 2-chloro-,2-hydroxy- or 2-alkoxycarboxylic acids and their derivatives where theR¹ radical, as long as it is inert under the reaction conditions, may bewidely varied as described above.

Owing to the easy accessibility, preference is given to using 2-aminoacids of the formula I such as phenylalanine, threonine, glutamic acid,proline, aspartic acid, alanine, ornithine, valine, leucine andisoleucine and their derivatives, and also 2-hydroxy- and2-chlorocarboxylic acids such as tartaric acid, lactic acid,2-chloropropionic acid and malic acid and derivatives thereof.

The catalysts used for the process according to the invention comprisepalladium and rhenium or platinum and rhenium. They may be used for thehydrogenation according to the invention with or without catalystsupport. They may additionally comprise at least one further elementhaving an atomic number of from 23 to 82.

Further elements for this purpose include titanium, vanadium, chromium,manganese, iron, cobalt, nickel, copper, zinc, zirconium, molybdenum,silver, tin, tungsten, lead, lanthanum and cerium, preferably silver,tungsten, molybdenum and tin, more preferably silver and tin.

The weight ratio of platinum or palladium to rhenium is preferably from100:1 to 0.01:1, more preferably from 50:1 to 0.05:1, in particular from10:1 to 0.1:1. The weight ratio of platinum or palladium to the at leastone further element is preferably from 100:1 to 10:1, more preferablyfrom 50:1 to 20:1.

The catalysts used according to the invention may comprise palladium,platinum, rhenium and any additional elements in different forms, forexample in elemental form, in the form of compounds of palladium,platinum, rhenium and the additional elements or in the form of anintermetallic compound of palladium, platinum, rhenium and theadditional elements.

The catalyst may be used as an unsupported or supported catalyst. Whenit is used as a supported catalyst, the support material may be anysuitable material, for example carbons, carbon blacks, graphites,silicon carbides, silicon dioxides, silicates, zeolites, titaniumdioxide, zirconium dioxide and aluminas. These supported catalysts maycomprise, for example, from 1 to 50% by weight of metal in elementalform or in the form of compounds. A particularly preferred supportmaterial is activated carbon pretreated oxidatively or with mineralacid. The preparation of such catalysts is described, for example, inEP-A-848 991 and U.S. Pat. No. 5,698,749.

If not applied to a support material, the catalysts may be used, forexample, in colloidal form or as a finely divided solid in the manneraccording to the invention. Examples of catalysts include finely dividedpalladium/rhenium, platinum/rhenium, palladium/rhenium/silver,platinum/rhenium/silver, palladium/rhenium/molybdenum,platinum/rhenium/tungsten, platinum/rhenium/tin particles, for examplein metallic form or in the form of their oxides, hydroxides, halides,nitrates, carboxylates, acetylacetonates or as amine complexes.

Particular preference is given to unsupported bimetallicpalladium/rhenium or platinum/rhenium catalysts. These may alsoadditionally comprise at least one further element of atomic number from23 to 82. They may be prepared, for example, by reduction of mixtures ofplatinum oxide or palladium oxide and rhenium oxide with a reducingagent, for example hydrogen. A third metal may be deposited in thepreparation of the catalyst or in situ, during the hydrogenationreaction. The preparation of such catalysts is described, for example,in WO 98/52891.

In a preferred embodiment of the process according to the invention, theabove-described optically active starting materials are hydrogenated inthe presence of an organic or inorganic acid. In general, the additionof acid is from 0.5 to 1.5 equivalents, more preferably from 1 to 1.3equivalents, based on 1 equivalent of any basic group present in thestarting materials. Examples of useful organic acids include aceticacid, propionic acid and adipic acid. Preference is given to addinginorganic acids, especially sulfuric acid, hydrochloric acid andphosphoric acid. The acids may be used, for example, as such, in theform of aqueous solutions or in the form of their separately preparedsalts with the starting materials to be hydrogenated, for example assulfates, hydrogensulfates, hydrochlorides, phosphates, mono- ordihydrogenphosphates.

Based on 1 mol of optically active starting compound used, it ispossible to use, for example, from 0.1 to 10 g of the catalysts usedaccording to the invention comprising platinum or palladium, rhenium andoptionally additional metals or from 1 to 50 g of the supportedcatalysts.

In general, the process according to the invention is carried out in thepresence of a solvent for the optically active starting materials of theformula I. Examples of useful solvents include water, water-miscibleorganic solvents and mixtures of both. Useful water-miscible solventsinclude lower alcohols having from 1 to 4 carbon atoms andwater-miscible ethers, e.g. tetrahydrofuran or dioxane. Preferredsolvents are water and mixtures which comprise water and lower alcoholsand/or tetrahydrofuran.

The process according to the invention may be carried out, for example,at temperatures in the range from 30 to 140° C. and pressures in therange from 5 to 300 bar. Preference is given to temperatures from 50 to130° C. and pressures from 10 to 280 bar. Particular preference is givento temperatures from 60 to 120° C. and pressures from 50 to 250 bar.

The reaction is over when no more hydrogen is taken up. Typically, thehydrogenation time is from 0.5 to 8 hours.

To work up the reaction mixture, it may, for example, be initiallycooled, the catalyst may be removed, for example by filtration, and thevolatile constituents present such as solvent and water of reaction maybe partly or fully removed by distillation, optionally under reducedpressure. In the case of 2-aminocarboxylic acids as starting compounds,it is possible to release the aminoalcohol from its salt from theresidue with base, e.g. aqueous alkali metal hydroxide solution oralcoholic alkoxide solution, remove the precipitated salt andfractionate the filtrate under reduced pressure. Like the solvent, thecatalyst removed can be reused.

The process according to the invention may be carried out continuously,semicontinuously or batchwise.

EXAMPLES

General Hydrogenation Procedure

In a metal autoclave, 0.1 g of PtO₂ and 0.2 g of Re₂O₇, suspended in 9 gof water, are initially charged and compressed with 60 bar of hydrogen.The suspension is stirred at 270° C. for 1 hour and decompressed aftercooling, and 1 g of the compound to be hydrogenated is added.Hydrogenation is then effected under the conditions specified below.

Inventive Examples 1 to 3

Preparation of (S)-leucinol

In accordance with the procedure given, 1 g of enantiomerically pure(L)-leucine (99.9% e.e.) was hydrogenated together with 0.5 g ofconcentrated sulfuric acid. The reaction conditions are summarized inTable 1:

TABLE 1 Inv. Pressure Temperature Reaction time example [bar] [° C.] [h]1 100 60 5 2 100 80 5 3 100 100 5

To determine the enantiomeric excesses, samples of the reactioneffluents were neutralized with sodium hydrogencarbonate,trifluoroacetylated and subsequently analyzed by means of gaschromatography using a chiral Cyclodex GTA column. The enantiomericexcesses in all three examples were determined to be greater than 99%e.e.

Inventive Example 4

Preparation of (S)-1,2-propanediol

In accordance with the procedure given above, 1 g of enantiomericallypure (L)-lactic acid (99.9% e.e.) was hydrogenated at a temperature of80° C. and 200 bar of hydrogen pressure for 5 hours.

The enantiomeric excess of the reaction effluent was determined by meansof gas chromatography using a Chirasil-Dex capillary to be greater than99% e.e.

Inventive Example 5

Preparation of S-1,2,4-butanetriol

A metal autoclave was initially charged with a suspension of 1.6 g ofPtO₂ and 4 g of Re₂O₇ in 50 g of water which was pressurized with 60 barof hydrogen and stirred at 270° C. and 124 bar for 1 hour. Aftercooling, the mixture was decompressed, 24 g of L(−)-malic acid in 100 mlof water were added and hydrogenation was subsequently effected at 100°C. and a pressure of 250 bar for 12 hours. S-1,2,4-butanetriol wasobtained in a yield of 40.8% and with an enantiomeric excess of 97.2%e.e.

Inventive Example 6

Preparation of S-alaninol

A metal autoclave was initially charged with a suspension of 0.4 g ofPtO₂ and 1 g of Re₂O₇ in 50 g of water which was pressurized with 60 barof hydrogen and stirred at 270° C. and 125 bar for 1 hour. Aftercooling, the mixture was decompressed, 24 g of L-alanine and 13.8 g ofconcentrated sulfuric acid in 100 ml of water were added andhydrogenation was subsequently effected at 60° C. and a pressure of 200bar for 12 hours. At a conversion of 14%, alaninol was obtained with anenantiomeric excess of 99.4% e.e.

Comparative Example 1

Hydrogenation of Enantiomerically Pure (L)-lactic Acid Without Re₂O₇

Inventive example 4 was carried out under the given reaction conditionsbut with the omission of 0.2 g of Re₂O₇. The gas chromatography analysisshowed that only about 1% of the (L)-lactic acid had been converted to1,2-propanediol.

1. A process for preparing optically active 2-amino-, 2-chloro-,2-hydroxy- or 2-alkoxy-1-alkanols by catalytically hydrogenatingoptically active 2-amino-, 2-chloro-, 2-hydroxy- and 2-alkoxycarboxylicacids or their acid derivatives, which comprises carrying out thehydrogenation in the presence of catalysts comprising palladium andrhenium or platinum and rhenium.
 2. The process according to claim 1,wherein optically active 2-amino-, 2-chloro-, 2-hydroxy- or2-alkoxycarboxylic acids or their esters of the formula I

where the radicals are defined as follows: R¹: straight-chain orbranched C₁–C₁₂-alkyl, C₇–C₁₂-aralkyl or C₆–C₁₀-aryl, each of which maybe substituted by NR³R⁴, OH, and/or COOH, R²: hydrogen, straight-chainor branched C₁–C₁₂-alkyl or C³–C₈-cycloalkyl, X: chlorine, NR⁵R⁶ or OR⁷,R³, R⁴, R⁵ and R⁶: each independently hydrogen, straight-chain orbranched C₁–C₁₂-alkyl, C₁₂–C₁₂-aralkyl, C₆–C₁₀-aryl, C₃–C₈-cycloalkyl orC₃–C₈-cycloalkyl in which one CH₂ group is replaced by O or NR⁸, R³ andR⁴ and also R⁵ and R⁶: also each independently together —(CH₂)_(m)—,where in is an integer from 4 to 7, R¹ and R⁵: also together —(CH₂)_(n)—where n is an integer from 2 to 6, R⁷: hydrogen, straight-chain orbranched C₁–C¹²-alkyl or C₃–C₈-cycloalkyl, R¹ and R⁷: also together—(CH₂)_(n)—, where n is an integer from 2 to 6 and R⁸: hydrogen,straight-chain or branched C₁–C₁₂-alkyl, C₇–C₁₂-aralkyl or C₆–C₁₀-aryl,or their acid anhydrides are used and hydrogenated to the correspondingoptically active alcohols of formula II

in which R¹ and X are each as defined above.
 3. The process according toclaim 1, wherein the palladium/rhenium or platinum/rhenium catalystscomprise at least one element from the group of the elements titanium,vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc,zirconium, molybdenum, silver, tin, tungsten, lead, lanthanum andcerium.
 4. The process according to claim 1, wherein thepalladium/rhenium or platinum/rhenium catalysts comprise at least oneelement from the group of the elements silver, molybdenum, tungsten andtin.
 5. The process according to claim 1, wherein the palladium/rheniumor platinum/rhenium catalysts are used unsupported or applied to asupport.
 6. The process according to claim 1, wherein the weight ratioof the palladium or platinum to rhenium is from 100:1 to 0.01:1.
 7. Theprocess according to claim 1, wherein the weight ratio of the palladiumor platinum to rhenium is from 50:1 to 0.05:1.
 8. The process accordingto claim 3, wherein the weight ratio of the palladium or platinum to theat least one element from the group of elements is from 100:1 to 10:1.9. The process according to claim 1, wherein the hydrogenation iscarried out in the presence of an acid.
 10. The process according toclaim 1, wherein the hydrogenation is carried out at a temperature offrom 30° to 140° C.
 11. The process according to claim 2, wherein thecompound of formula I is selected from the group consisting ofphenylalanine, threonine, glutamic acid, praline, aspartic acid,alanine, ornithine, valine, leucine, isoleucine, taz-taric acid, lacticacid, 2-chloropropionic acid, malic acid and the acid derivatives ofeach thereof.
 12. The process according to claim 4, wherein the weightratio of the palladium or platinum to the at least one element from thegroup of elements is from 100:1 to 10:1.
 13. The process according toclaim 4, wherein the hydrogenation is carried out in the presence of anacid and at a temperature of from 30° to 140° C.
 14. The processaccording to claim 1, wherein the 2-aminocarboxylic acids are selectedfrom the group consisting of phenylalanine, threonine, glutamic acid,proline, aspartic acid, alanine, ornithine, valine, leucine, isoleucine,the 2-hydroxycarboxylic acids are selected from tartaric acid, lacticacid or malic acid, and the 2-chlorocarboxylic acid is 2-chloropropionicacid.
 15. The process according to claim 1, wherein the weight ratio ofthe palladium or platinum to rhenium is from 10:1 to 0.1:1.
 16. Theprocess according to claim 4, wherein the weight ratio of the palladiumor platinum to rhenium is from 10:1 to 0.1:1.
 17. A process forpreparing optically active 2-amino-, 2-chloro-, 2-hydroxy- or2-alkoxy-1-alkanols by catalytically hydrogenating optically active,2-substituted-carboxylic acids selected from the group consisting of2-amino-, 2-chloro-, 2-hydroxy- and 2-alkoxycarboxylic acids or the acidderivatives of each thereof, which comprises carrying out thehydrogenation in the presence of an unsupported bimetallic catalystcomprising palladium and rhenium or platinum and rhenium, wherein thecatalysts are prepared from the mixtures of platinum oxide or palladiumoxide, and rhenium oxide in the presence of a reducing agent.
 18. Theprocess according to claim 17, wherein the 2-aminocarboxylic acids areselected from the group consisting of phenylalanine, threonine, glutaricacid, proline, aspartic acid, alanine, ornithine, vaunt, leucine,isoleucine, the 2-hydroxycarboxylic acids are selected from tartaricacid, lactic acid or malic acid, and the 2-chlorocarboxylic acid is2-chloropropionic acid.